Reconstituted high density lipoprotein (R-HDL) has been shown in vitro and in vivo, to have antiendotoxin properties. The hypothesis is that lipoproteins bind, neutralize, and increase clearance of endotoxin. Being a natural, biologic product, R-HDL could be used prophylactically, to prevent septic shock in high risk patients and in chemotherapy-induced neutropenia, or therapeutically to treat septic shock. To test this hypothesis, in a controlled, randomized trial, we investigated the effects of R-HDL on survival, endotoxemia, cytokine production, and pathophysiologic and metabolic events in our canine model of septic shock. At 0.5, 8, and 16 h after implantation of a E. coli infected clot, canines received intravenous R-HDL control lipid, or human serum albumin (HSA). Animals treated with R-HDL had lower levels of circulating endotoxin and tumor necrosis factor (TNF) and a smaller decrease in white blood cell counts than did animals treated with lipids and HSA. Survival times of lipid- and HSA-treated animals were similar and were significantly greater than those of R-HDL treated animals. R-HDL-treated animals had significantly greater abnormalities in liver function compared to lipid- and HSA-treated animals. In normal animals, R-HDL caused transient elevation of liver enzymes, and in animals given sterile clot intraperitoneally, R-HDL caused seizures. Thus, this preparation of R-HDL had antiendotoxin effects but also had hepatic and neurologic toxicities. We now plan to investigate a different preparation of high density lipoprotein (HDL) which has a different chemical composition than that used in this canine experiment. This new preparation was manufactured in such a way to limit the potential of liver and neurological toxicity. First, we will investigate the new R-HDL preparation in small animal models of live infection (rats), and subsequently, if no toxicity and beneficial antiendotoxin effects are documented, in our canine model of septic shock. If toxicities associated with R-HDL can be reduced, its antiendotoxin effects may potentially be used prophylactically in high risk patients, or therapeutically in patients with established septic shock.